The purpose of this Midcareer Investigator Award is to allow Dr. Wilkinson to: 1) devote more time to mouse pathobiology research and to mentoring beginning investigators and 2) to increase the pool of mouse pathobiologists. Dr. Wilkinson's long term career goal is to continue to contribute in significant ways to biomedical research by bringing his unique background and expertise to problems related to murine pathobiology. Dr. Wilkinson has established an extremely productive collaboration with investigators in the field and has access to the vast mouse mutation resource of ORNL. Having established a strong program in this area, he plans to continue to collaborate with the best molecular biologists, geneticists, developmental biologists, and other scientists to define the role of genes in disease. The Specific Aims of the proposed studies are: 1) to continue studies of liver and pancreatic stem cells using the unique reagents available for previous work with the transgenic TgN737 mouse [a) to determine if putative stem cells are capable of bipotential differentiation in the liver and pancreas; and b) to determine the role of oval cells and the Tg737 gene in hepatocellular carcinogenesis]; 2) to further characterize the nature of the CD4+ T cell abnormality in scurfy mice [a) to define hyper responsiveness of scurfy CD4+ T cells; b) to determine if Sf1OVA mice can develop peripheral tolerance; c) to determine if normal T cells can modulate the activity of scurfy T cells; and d) to characterize the immune response of transgenic mice that express the scurfy gene product from an inducible promoter and/or a T cell specific promoter]; 3) to continue to provide pathology support for other murine pathobiologists and identify and characterize the phenotype of recently identified mutant mice and those being generated as part of a genome wide saturation mutagenesis effort at ORNL.